1. Field of the Invention
The present invention relates to a biodegradable copolymer and a biodegradable polymeric micelle composition containing the copolymer. The biodegradable polymeric micelle composition has good drug and bioactive agent delivery characteristics and is suitable for use in drug delivery or cosmetic applications.
2. Description of the Related Art
Many biodelivery technologies (such as encapsulation and delivery) have been developed for clinical applications, is which prevent pharmaceutical drugs, bioactive substances, or living cells from deterioration by the physiological environment of the body during the course of delivery or to enable slow and stable release in the body. Drugs or bioactive substances are typically encapsulated in bioresorbable polymeric material, such as, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), or lactic acid/glycolic acid copolymer (PLGA) in many commercialized techniques before being administrated to organisms.
PLA and PGA, linear polymeric material, have been used mainly for drug and bioactive substance encapsulation and delivery. However, the encapsulation efficiency of hydrophilic drugs and peptides with high molecular weight are poor due to hydrophobicity. Therefore, many researches are oriented to amphiphilic biodegradable material to overcome this problem.
A. S. Sawhney et al., Macromolecules, Vol 26, No. 4, 581-589 (1993) disclose macromers having a polyethylene glycol central block, extended with oligomers of α-hydroxy acids such as oligo(D,L-lactic acid) or oligo(glycolic acid) and terminated with acrylate groups. Using photoinitiators, these multifunctional macromers can be crosslinked under ultraviolet. The rates of biodegradation upon hydrolysis can be tailored by appropriate choice of the PEG and the oligo(α-hydroxy acid) from less than 1 day to up to 4 months.
Okada et al., in Japanese Patent 2-78629 (1990), disclose a segment-type linear block copolymer formed from PLA or PLGA and PEG. The molecular weight range for PLGA is 400 to 5,000 and for PEG, 200 to 2,000. The reaction is performed under high temperature and the reaction product could precipitate and form a hydrogel in water above room temperature.
T. Matsuda, ASAIO Journal, M512-M517 (1993) used a biodegradable polymeric gel to deliver a potent peptidyl antiproliferative agent. The gel was a highly viscous fluid of a linear block copolymer composed of PLA and PEG block segments and used as a drug carrier.
L. Martini et al., J. Chem. Soc., Faraday Trans., 90(13), 1961-1966 (1994) synthesized very low molecular weight ABA type tri-block copolymers by copolymerizing hydrophobic poly(ε-caprolactone) (PCL) block and hydrophilic PEG block, forming a PCL-PEG-PCL tri-block copolymer. Different cloud points were observed with various components. For example, the cloud points of 2 wt % aqueous solutions of the copolymers were 65° C. and 55° C. for PCL-PEG-PCL (450:4000:450) and PCL-PEG-PCL (680:4000:680), respectively. When the molecular weight of PCL was higher, the in vivo degradation rate was slower. A slow degradation was favorable to the drug release control efficiency.
U.S. Pat. No. 6,201,072 issued to MacroMed Company discloses an ABA- or BAB-linear type tri-block copolymer containing a biodegradable polyester (block A) and PEG (block B). The tri-block copolymer is water soluble and possesses reverse thermal gelation properties when the copolymer molecular weight is between 2000 and 4990 and wt % of the hydrophobic segment is between 51 to 83%. A drug delivery composition containing said copolymer is also disclosed. ReGel®, an injectable drug release system developed using PLA-PEG-PLA tri-block copolymer by MacroMed company has been approved by the FDA for years.
In view of the above description, a linear amphiphilic copolymer has been disclosed, but neither a branched amphiphilic copolymer having a hydrophobic segment as a core nor a polymeric micelle composition containing a linear or branched amphiphilic copolymer in use of drug delivery has been disclosed.
G. S. Kwon et al., in Pharmaceutical Research, Vol. 12, No. 2, 192-195 (1995) and Journal of Controlled Release, Vol. 48, 195-201 (1997) reported micelles of PEO-PBLA copolymer with a diameter of about 20 to 40 nm. The encapsulating rate for the micelles to encapsulate a highly lipid soluble antitumor agent, adriamycin, could be 5-12% (w/w). Compared with un-encapsulated adriamycin, the drug encapsulated with PEO-PBLA copolymer exhibited an extended recycling period in vivo and an improved phagocytic efficiency on cancer cells. In addition, the degradation rate of the drug decreased after encapsulation, thus, the micelles could be deemed as a storage unit for the drug and a long-term release effect could be achieved.
T. Minko et al., International Journal of Cancer, Vol. 86, 108-117 (2000) reported an ex vivo experiment using human ovarian carcinoma cell line and the comparison of administrating an antitumor drug, adriamycin (i.e. doxorubicin), by means of conventional methods and by means of micelles of HPMA copolymer with adriamycin attached. The result indicated a higher antitumor activity and lower systemic toxicity of HPMA copolymer-bound adriamycin when compared with free adriamycin.
S. C. Kim et al., Journal of Controlled Release, Vol. 72, 191-202 (2001) reported micelles formed by encapsulating paclitaxol in mPEG-PDLLA copolymer molecules. The result of the experiment for the ovarian carcinoma cell line and the human breast cancer cell line indicated that the dosage form of paclitaxol in the micelles reduced cytotoxicity, improved maximum tolerated dose (MTD), improved median lethal dose (LD50) and improved antitumor activity, as compared with un-encapsulated paclitaxol.